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DMD: Phase 2 Drisapersen Results Encouraging

Update March 27, 2014: Prosensa and United Parent Projects Muscular Dystrophy jointly presented an educational webinar for patients and families affected by Duchenne muscular dystrophy on March 25, 2014. The approximately one-hour presentation is archived at Events & Presentations on the Prosensa site and includes a thorough discussion of Prosensa's plans for drisapersen and other exon-skipping compounds in its pipeline, as well as a question-and-answer session. Highlights are that Prosensa hopes to begin re-dosing with drisapersen for boys previously treated in trials with this drug during the third quarter of 2014; that other Prosensa studies involving DMD exon-skipping drugs are continuing but may undergo some adaptation based on the full evaluation of drisapersen results; and that, even it becomes clear that prolongation of walking requires early treatment with drisapersen, it is possible that later drisapersen treatment, in more advanced patients, could benefit arm or pulmonary function. Questions can be directed to Prosensa by sending email to patientinfo@prosensa.nl.

Update March 22, 2014: This story was updated to reflect additional information provided by principal inhvestigator Craig McDonald.

Drisapersen, an experimental drug in development for Duchenne muscular dystrophy (DMD) by Dutch biotechnology company Prosensa, has shown encouraging results in a phase 2, U.S.-based clinical trial involving 51 participants.

Drisapersen, an exon-skipping compound, targets and blocks a section of the dystrophin gene called exon 51 and is designed to cause patients with mutations near this part of the gene to make a short, but still functional, version of the dystrophin protein. A deficiency of this protein in skeletal and cardiac muscle cells is the underlying cause of DMD.

The results for this phase 2 trial contrast with the negative results for a phase 3 trial of drisapersen announced in September 2013 and will likely require closer scrutiny before they are fully understood. The phase 3 trial did not show benefit on tests of walking distance or motor function in a trial involving 186 DMD-affected boys.

MDA has been funding development of exon-skipping strategies for DMD since the 1990s but was not directly involved in this study.

High-dose drisapersen group showed stabilized walking distance

The phase 2 trial showed that boys with DMD who received 6 milligrams per kilogram of body weight once a week (the high-dose group) experienced stabilization and even some improvement in their muscle function as measured by the six-minute walk test (distance that can be walked in six minutes) after 24 weeks. They maintained this stabilization for another 24 weeks after treatment was stopped.

A “clinically meaningful” difference between the 6-milligram per kilogram group and the placebo group at 24 weeks and 48 weeks was seen, Prosensa said.

The study included 51 boys with DMD who were at least 5 years old, were able to rise from the floor without help in less than 15 seconds, and were able to walk without assistance.

“The maintenance of the clinically meaningful treatment benefit in the 24-week follow-up phase is very encouraging evidence for the drug’s ability to produce prolonged stabilization of disease and may indicate that, at the 6 milligram per kilogram once weekly dose, the drug has a long-term treatment effect that helps delay disease progression in younger, less severe boys,” said Craig McDonald, principal investigator for the phase 2 trial and a professor of physical medicine and rehabilitation at the University of California, Davis.

In comments made to MDA, McDonald said the median age in the large-scale, phase 3 trial was 8 and that many patients did not start treatment until they were 10 years old. He said the median age in the phase 2, U.S. trial was 6.5 years. He also said the phase 3 trial participants walked an average of 337 meters in six minutes when they entered the study, while the phase 2, U.S. participants walked an average of 396 meters at study entry.

Drisapersen, he speculates, may work better in younger DMD patients than in older ones. “The data emerging are saying that, at least when you have walking distance as your trial endpoint, younger patients seem to do better than patients who are older and have more difficulty walking at the start. In addition, the benefits in the phase 3 trial seem to be more evident with longer-term follow-up beyond a year."

McDonald added that he hopes Prosensa will begin re-dosing soon as part of the previously initiated extension trials. "We need to get patients back on the drug," he said.